CA2211499A1 - Methods for the manufacture of amorphous cefuroxime axetil - Google Patents
Methods for the manufacture of amorphous cefuroxime axetilInfo
- Publication number
- CA2211499A1 CA2211499A1 CA002211499A CA2211499A CA2211499A1 CA 2211499 A1 CA2211499 A1 CA 2211499A1 CA 002211499 A CA002211499 A CA 002211499A CA 2211499 A CA2211499 A CA 2211499A CA 2211499 A1 CA2211499 A1 CA 2211499A1
- Authority
- CA
- Canada
- Prior art keywords
- cefuroxime axetil
- solvent
- water
- amorphous
- highly polar
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
A process for preparing pure amorphous cefuroxime axetil comprising the steps of dissolving crystalline cefuroxime axetil in a highly polar organic solvent and adding the resulting solution to water, or alternatively, dissolving crystallinecefuroxime axetil in a highly polar solvent and adding small quantities of waterto the organic solution and adding the resulting organic-aqueous solution to water.
Description
CA 02211499 1997-07-2~
METHODS FOR THE MANUFACTURE OF
AMORPHOUS CEFUROXIME AXETIL
FIELD OF THE INVENTION
This invention relates to novel processes for the manufacture of amorphous cefuroxime axetil.
BACKGROUND OF THE INVENTION
Cefuroxime axetil, [R-6a,7,B(Z)]]-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-acetoxyethyl ester is the 1-acethyloxyethyl ester of cefuroxime.
Cefuroxime axetil can be classified as a member of the second generation 15 cephalosporins and is ~-lactam antibacterial agent. Cefuroxime axetil has the following structure (I) 2 / ;X
,o~l, CA 02211499 1997-07-2~
British Patent 1,571,683 discloses the preparation of cefuroxime axetil in crystalline form by precipitation from a solution of ethyl acetate with diethyl ether or diisopropyl ether. U.S. Patent 4,820,833 also describes the preparation of cefuroxime axetil in crystalline form by crystallization from ethyl acetate withsubsequent addition of dissopropyl ether to obtain more crystalline material.
U.S. Patent 4,820,833 also discloses that the amorphous form of cefuroxime axetil has higher bioavailability than crystalline cefuroxime axetil while maintaining adequate chemical stability upon storage. Accordingly, for commercial purpose the amorphous form is used rather than the crystalline form.
In US patent 4,820,833 (serial number 938,140), the crystalline product is dissolved in an organic solvent and subsequently obtained in amorphous form by spray drying. Various examples of precipitation of amorphous cefuroxime axetil have also been provided.
U.S. patent 5,013,833 which issued out of a divisional application of serial number 938,140 describes the preparation of amorphous cefuroxime axetil by solvent precipitation of the product dissolved in an organic solvent (or a mixture thereof in water).
In U.S. Patent 4,820,833 and U.S. Patent 5,013,833 the organic solvents include ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters, chlorinated solvents, or a homogeneous mixture of at least two such solvents.
CA 02211499 1997-07-2~
The precipitation processes referred to in U.S. patent 5,013,833 while producingcefuroxime axetil substantially in amorphous form have a number of disadvantages:
1. The use of very large volumes of a solvent such as dichloromethane (40 ml/g) and diisopropyl ether (32.5 ml/g) that by their toxicity and possibility of explosive peroxide formation may render the process not commercially feasible.
2. Precipitation of the product dissolved in acetone from water requires very elaborate experimental set up in the laboratory (filtration of the solution of the product prior to its addition to water or spray drying, high rate of stirring, exact rate of addition, continuous froth collection, the necessity to harvest the product immediately) which renders the reaction arduous and difficult to manage in a large scale manufacturing environment. In fact, even under a manageable laboratory environment, only a substantially amorphous product could be obtained. Further, the amount of the crystalline form varies substantially with slight changes in the above-mentioned parameters.
It has now been surprisingly found that by dissolving crystalline cefuroxime axetil in a minimum volume of a highly polar organic solvent and adding the resulting solution to water or by dissolving crystalline cefuroxime axetil in a minimum 25 volume of a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water, amorphous cefuroxime axetil could be obtained.
The present processes have a number of major advantages over the existing 30 procedures.
. CA 02211499 1997-07-2~
First, because of excellent solubilizing properties of the highly polar solventsused in this invention, there is no need for filtration of the solution containing the product prior to its precipitation in amorphous form. Filtration is crucial in the precipitation processes disclosed in U.S. Patent 5,013,833 because minute quantity of undissolved crystalline material could act as seeds and cause the precipitation of at least some of the material in its thermodynamically more stable crystalline form rather than the high energy amorphous form which may explain why only "substantially amorphous" material could be obtained by the previously disclosed precipitation processes.
Second, very small volume of a highly polar solvent is required to achieve totaldissolution, thus rendering the present processes more economical and environmentally safe.
Third, the experimental conditions are simple and applicable to large scale production.
Fourth, the present processes are reproducible and consistently afford amorphous [as examined by powder x-ray diffraction and IR spectrum (Figures 1 and 2)].
Fifth, the amorphous product generated by the processes of the present invention is highly pure and shows an acceptable ratio of the R and S
diasteroisomers as defined by US Pharmacopoeia 23 (page 315). The mixture has improved solubility as compared with amorphous R isomer or amorphous S
isomer alone.
Sixth, the yields of the amorphous product obtained when practising the invention are very high and within the range of 84 to 96%.
CA 02211499 1997-07-2~
BRIEF DESCRIPTION OF THE INVENTION
Amorphous cefuroxime axetil is conveniently obtained by dissolving the 5 crystalline form in a highly polar solvent such as DMSO, DMF, or preferably formic acid and adding the resulting solution at 0-20 ~C to water with stirring.The precipitated amorphous material is filtered, pulped in small quantities of water and filtered (twice) to remove residual polar solvent. The damp cake is then dried with forced nitrogen at 3-35 ~C and then under vacuum at 35 ~C to 10 obtain aniorphous cefuroxime axetil in high yields. Figure 1 is a X-ray powder diffraction of amorphous cefuroxime as produced by the invention. Figure 2 is a IR spectrum of amorphous cefuroxime axetil.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention a process for the preparation of pure amorphous cefuroxime axetil is provided.
The starting material in the present invention is crystalline cefuroxime axetil and 20 more particularly a 50:50 mixture of R and S isomers of the carbon forming the ester function with the 2-carboxyl group of cefuroxime, which is commercially available.
The amorphous cefuroxime axetil in accordance with the invention contains less 25 than 0.60io of impurities. The major impurity associated with the process is usually in the range of 0.3-0.5% and is the anti form cefuroxime axetil in whichthe CH3-0- group of the oxime is cis with the furil ring:
CA 02211499 1997-07-2~
/~ S~
N // N Ob,NH2 (I) O~ ~
I~ ~
~ \
The ar"o,l l ,ous form of cefuroxi",e axetil is a mixture of its R and S isomers in which the ratio of peak responses R should be between 0.48 and 0.55 as 15 dete~",.. ,ed by the following equation.
R = rA/(rA + rB) The solvent or mixture of solvents employed to dissolve the crystalline form of 20 cefuroxime axetil will be chosen among organic solvent of high polarity. Suitable solvents include dimethyl sulfoxide dimethyl fc,r",an,ide and preferably formic acid. The solvent if desired may be heated. The concentration of cefuroxime axetil in the solvent is as high as possible and p~:rer~bly no less than 0.3 9/ ml of the solvent.
The process comprises the dissolution of crystalline cefuloxi,l,e axetil in a highly polar organic solvent. The resulting solution is then added to water while stirring.
Alternatively after dissolution of crystalline cefuroxime axetil water may be added to the polar organic solution which is then added to water. The addition 30 of the resulting solution to water is carried out between 0~ and 40~C and preferably between 0 and 4~C.
CA 02211499 1997-07-2~
The amorphous cefuroxime axetil produced according to the invention has been identified by powder x-ray diffraction and IR spectroscopy (Figures 1 and 2).
5 The transition temperature for the conversion of the amorphous form of cefuroxime axetil to its crystalline form appears to be low. Accordingly, due caution must be exercised to maintain the vacuum oven temperatures of below 45~C during the final drying stage.
10 The invention will be more fully understood by the following examples which illustrate the present invention, but are not to be considered limiting to the scope of the invention.
Cefuroxime axetil (5 g) was dissolved in 12 ml dimethyl sulfoxide by gentle heating. The resulting solution was added dropwise to deionized water (100 ml) cooled to 4~C with good mechanical stirring. A thick slurry formed which was 20 filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered andwashed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 40-45~C for 48 hours. Yield 4.3 9 (85%).
Cefuroxime axetil (5 9) was dissolved in 15 ml dimethyl sulfoxide by gentle 30 heating. Deionized water (6 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (90 ml) cooled to 4~C with good mechanical stirring. A thick slurry formed which was filtered and washed with a CA 02211499 1997-07-2~
small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 4045 ~C for 48 hours. Yield 4.7 9 (95 %).
Cefuroxime axetil (5 g) was dissolved in 20 ml dimethyl formamide by gentle heating. The resulting solution was added dropwise to deionized water (150 ml) cooled to 4 ~C with good mechanical stirring. A thick slurry formed which was filtered and washed with deionized water. The damp cake was pulped in deionized water (100 ml) for 30 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under vacuum at 4045 ~C for 48 hours. Yield 4.15 9 (83 %).
Cefuroxime axetil (5 9) was dissolved in 25 ml dimethyl formamide by gentle heating. Deionized water (9 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (110 ml) cooled to 4 ~C with good mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 4045 ~C for 48 hours. Yield 4.4 9 (89%).
CA 02211499 1997-07-2~
Cefuroxime axetil (100 g) was dissolved in 152 ml 88% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) withgood mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 ~C for 48 hours. Yield 90 g (90%).
Cefuroxime axetil (100 g) was dissolved in 105 ml 96% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) withgood mechanical stirring. A thick slurry formed which was filtered and washed 20 with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 ~C for 48 hours. Yield 90 g (90%).
METHODS FOR THE MANUFACTURE OF
AMORPHOUS CEFUROXIME AXETIL
FIELD OF THE INVENTION
This invention relates to novel processes for the manufacture of amorphous cefuroxime axetil.
BACKGROUND OF THE INVENTION
Cefuroxime axetil, [R-6a,7,B(Z)]]-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-acetoxyethyl ester is the 1-acethyloxyethyl ester of cefuroxime.
Cefuroxime axetil can be classified as a member of the second generation 15 cephalosporins and is ~-lactam antibacterial agent. Cefuroxime axetil has the following structure (I) 2 / ;X
,o~l, CA 02211499 1997-07-2~
British Patent 1,571,683 discloses the preparation of cefuroxime axetil in crystalline form by precipitation from a solution of ethyl acetate with diethyl ether or diisopropyl ether. U.S. Patent 4,820,833 also describes the preparation of cefuroxime axetil in crystalline form by crystallization from ethyl acetate withsubsequent addition of dissopropyl ether to obtain more crystalline material.
U.S. Patent 4,820,833 also discloses that the amorphous form of cefuroxime axetil has higher bioavailability than crystalline cefuroxime axetil while maintaining adequate chemical stability upon storage. Accordingly, for commercial purpose the amorphous form is used rather than the crystalline form.
In US patent 4,820,833 (serial number 938,140), the crystalline product is dissolved in an organic solvent and subsequently obtained in amorphous form by spray drying. Various examples of precipitation of amorphous cefuroxime axetil have also been provided.
U.S. patent 5,013,833 which issued out of a divisional application of serial number 938,140 describes the preparation of amorphous cefuroxime axetil by solvent precipitation of the product dissolved in an organic solvent (or a mixture thereof in water).
In U.S. Patent 4,820,833 and U.S. Patent 5,013,833 the organic solvents include ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters, chlorinated solvents, or a homogeneous mixture of at least two such solvents.
CA 02211499 1997-07-2~
The precipitation processes referred to in U.S. patent 5,013,833 while producingcefuroxime axetil substantially in amorphous form have a number of disadvantages:
1. The use of very large volumes of a solvent such as dichloromethane (40 ml/g) and diisopropyl ether (32.5 ml/g) that by their toxicity and possibility of explosive peroxide formation may render the process not commercially feasible.
2. Precipitation of the product dissolved in acetone from water requires very elaborate experimental set up in the laboratory (filtration of the solution of the product prior to its addition to water or spray drying, high rate of stirring, exact rate of addition, continuous froth collection, the necessity to harvest the product immediately) which renders the reaction arduous and difficult to manage in a large scale manufacturing environment. In fact, even under a manageable laboratory environment, only a substantially amorphous product could be obtained. Further, the amount of the crystalline form varies substantially with slight changes in the above-mentioned parameters.
It has now been surprisingly found that by dissolving crystalline cefuroxime axetil in a minimum volume of a highly polar organic solvent and adding the resulting solution to water or by dissolving crystalline cefuroxime axetil in a minimum 25 volume of a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water, amorphous cefuroxime axetil could be obtained.
The present processes have a number of major advantages over the existing 30 procedures.
. CA 02211499 1997-07-2~
First, because of excellent solubilizing properties of the highly polar solventsused in this invention, there is no need for filtration of the solution containing the product prior to its precipitation in amorphous form. Filtration is crucial in the precipitation processes disclosed in U.S. Patent 5,013,833 because minute quantity of undissolved crystalline material could act as seeds and cause the precipitation of at least some of the material in its thermodynamically more stable crystalline form rather than the high energy amorphous form which may explain why only "substantially amorphous" material could be obtained by the previously disclosed precipitation processes.
Second, very small volume of a highly polar solvent is required to achieve totaldissolution, thus rendering the present processes more economical and environmentally safe.
Third, the experimental conditions are simple and applicable to large scale production.
Fourth, the present processes are reproducible and consistently afford amorphous [as examined by powder x-ray diffraction and IR spectrum (Figures 1 and 2)].
Fifth, the amorphous product generated by the processes of the present invention is highly pure and shows an acceptable ratio of the R and S
diasteroisomers as defined by US Pharmacopoeia 23 (page 315). The mixture has improved solubility as compared with amorphous R isomer or amorphous S
isomer alone.
Sixth, the yields of the amorphous product obtained when practising the invention are very high and within the range of 84 to 96%.
CA 02211499 1997-07-2~
BRIEF DESCRIPTION OF THE INVENTION
Amorphous cefuroxime axetil is conveniently obtained by dissolving the 5 crystalline form in a highly polar solvent such as DMSO, DMF, or preferably formic acid and adding the resulting solution at 0-20 ~C to water with stirring.The precipitated amorphous material is filtered, pulped in small quantities of water and filtered (twice) to remove residual polar solvent. The damp cake is then dried with forced nitrogen at 3-35 ~C and then under vacuum at 35 ~C to 10 obtain aniorphous cefuroxime axetil in high yields. Figure 1 is a X-ray powder diffraction of amorphous cefuroxime as produced by the invention. Figure 2 is a IR spectrum of amorphous cefuroxime axetil.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention a process for the preparation of pure amorphous cefuroxime axetil is provided.
The starting material in the present invention is crystalline cefuroxime axetil and 20 more particularly a 50:50 mixture of R and S isomers of the carbon forming the ester function with the 2-carboxyl group of cefuroxime, which is commercially available.
The amorphous cefuroxime axetil in accordance with the invention contains less 25 than 0.60io of impurities. The major impurity associated with the process is usually in the range of 0.3-0.5% and is the anti form cefuroxime axetil in whichthe CH3-0- group of the oxime is cis with the furil ring:
CA 02211499 1997-07-2~
/~ S~
N // N Ob,NH2 (I) O~ ~
I~ ~
~ \
The ar"o,l l ,ous form of cefuroxi",e axetil is a mixture of its R and S isomers in which the ratio of peak responses R should be between 0.48 and 0.55 as 15 dete~",.. ,ed by the following equation.
R = rA/(rA + rB) The solvent or mixture of solvents employed to dissolve the crystalline form of 20 cefuroxime axetil will be chosen among organic solvent of high polarity. Suitable solvents include dimethyl sulfoxide dimethyl fc,r",an,ide and preferably formic acid. The solvent if desired may be heated. The concentration of cefuroxime axetil in the solvent is as high as possible and p~:rer~bly no less than 0.3 9/ ml of the solvent.
The process comprises the dissolution of crystalline cefuloxi,l,e axetil in a highly polar organic solvent. The resulting solution is then added to water while stirring.
Alternatively after dissolution of crystalline cefuroxime axetil water may be added to the polar organic solution which is then added to water. The addition 30 of the resulting solution to water is carried out between 0~ and 40~C and preferably between 0 and 4~C.
CA 02211499 1997-07-2~
The amorphous cefuroxime axetil produced according to the invention has been identified by powder x-ray diffraction and IR spectroscopy (Figures 1 and 2).
5 The transition temperature for the conversion of the amorphous form of cefuroxime axetil to its crystalline form appears to be low. Accordingly, due caution must be exercised to maintain the vacuum oven temperatures of below 45~C during the final drying stage.
10 The invention will be more fully understood by the following examples which illustrate the present invention, but are not to be considered limiting to the scope of the invention.
Cefuroxime axetil (5 g) was dissolved in 12 ml dimethyl sulfoxide by gentle heating. The resulting solution was added dropwise to deionized water (100 ml) cooled to 4~C with good mechanical stirring. A thick slurry formed which was 20 filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered andwashed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 40-45~C for 48 hours. Yield 4.3 9 (85%).
Cefuroxime axetil (5 9) was dissolved in 15 ml dimethyl sulfoxide by gentle 30 heating. Deionized water (6 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (90 ml) cooled to 4~C with good mechanical stirring. A thick slurry formed which was filtered and washed with a CA 02211499 1997-07-2~
small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 4045 ~C for 48 hours. Yield 4.7 9 (95 %).
Cefuroxime axetil (5 g) was dissolved in 20 ml dimethyl formamide by gentle heating. The resulting solution was added dropwise to deionized water (150 ml) cooled to 4 ~C with good mechanical stirring. A thick slurry formed which was filtered and washed with deionized water. The damp cake was pulped in deionized water (100 ml) for 30 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under vacuum at 4045 ~C for 48 hours. Yield 4.15 9 (83 %).
Cefuroxime axetil (5 9) was dissolved in 25 ml dimethyl formamide by gentle heating. Deionized water (9 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (110 ml) cooled to 4 ~C with good mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 4045 ~C for 48 hours. Yield 4.4 9 (89%).
CA 02211499 1997-07-2~
Cefuroxime axetil (100 g) was dissolved in 152 ml 88% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) withgood mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 ~C for 48 hours. Yield 90 g (90%).
Cefuroxime axetil (100 g) was dissolved in 105 ml 96% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) withgood mechanical stirring. A thick slurry formed which was filtered and washed 20 with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 ~C for 48 hours. Yield 90 g (90%).
Claims (10)
1. Process of preparation of amorphous cefuroxime axetil which comprises the steps of:
(a) dissolving crystalline cefuroxime axetil in a highly polar organic solvent and adding the resulting solution to water; or (b) dissolving crystalline cefuroxime axetil in a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water.
(a) dissolving crystalline cefuroxime axetil in a highly polar organic solvent and adding the resulting solution to water; or (b) dissolving crystalline cefuroxime axetil in a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water.
2. The process of claim 1 wherein the dissolution of crystalline cefuroxime axetil is carried out in a volume of solvent only sufficient to dissolve crystalline cefuroxime axetil.
3. The process of claim 1 or 2 wherein the highly polar solvent is a sulfoxide.
4. The process of claim 1 or 2 wherein the sulfoxide is dimethyl sulfoxide.
5. The process of claim 1 or 2 wherein the highly polar solvent is an amide.
6. The process of claim 5 wherein the amide is selected from the group consisting of dimethyl formamide, dimethyl acetamide, or hexamethyl phosphoramide.
7. The process of claim 1 or 2 wherein the solvent is formic acid.
8. The process of claim 1 or 2 wherein the solvent is a homogeneous mixture of dimethyl sulfoxide and the amide.
9. The process of claim 1 or 2 wherein the addition of the resulting solution to water is carried out between 0 to 40°C.
10. The process of claim 9 wherein the addition is carried out between 0 to 4°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ299077 | 1996-07-26 | ||
| NZ299077A NZ299077A (en) | 1996-07-26 | 1996-07-26 | Preparation of amorphous cefuroxime axetil (a cephalosporin derivative) by dissolving crystalline cefuroxim axetil in a highly polar solvent, typically dmso and/or dmf |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2211499A1 true CA2211499A1 (en) | 1998-01-26 |
Family
ID=19925874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002211499A Abandoned CA2211499A1 (en) | 1996-07-26 | 1997-07-25 | Methods for the manufacture of amorphous cefuroxime axetil |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US5847118A (en) |
| CA (1) | CA2211499A1 (en) |
| NZ (1) | NZ299077A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN186539B (en) | 1997-09-29 | 2001-09-29 | Ranbaxy Lab Ltd | |
| EP0937727B1 (en) * | 1998-02-20 | 2002-01-30 | Fako Ilaclari A.S. | Process of preparation of soluble crystalline cefuroxime axetil |
| US6384213B1 (en) * | 1998-10-23 | 2002-05-07 | Ranbaxy Laboratories Limited | Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil |
| KR100363566B1 (en) * | 1998-11-20 | 2003-08-19 | 국제약품공업주식회사 | Process for preparing amorphous Sepuroxime Axetyl |
| IN190831B (en) * | 1999-03-19 | 2003-08-23 | Ranbaxy Lab Ltd | |
| KR100362230B1 (en) * | 2000-04-21 | 2002-11-23 | 주식회사 대웅제약 | Process for preparing amorphous cefuroxime axetil having a low melting point |
| KR100357816B1 (en) * | 2000-05-09 | 2002-10-18 | 보령제약 주식회사 | Process for the preparation of amorphous cefuroxime axetil and the isolation process thereof |
| ITMI20011766A1 (en) * | 2001-08-10 | 2003-02-10 | A & G Soluzioni Digitali S R L | DEVICE AND METHOD FOR SIMULATING THE PRESENCE OF ONE OR MORE SOURCES OF SOUNDS IN VIRTUAL POSITIONS IN THE THREE-DIM SOUND SPACE |
| ITMI20011763A1 (en) * | 2001-08-10 | 2003-02-10 | Antibioticos Spa | HIGH-PURITY CEFUROXIME AXELITE PREPARATION PROCESS |
| HRP20020923A2 (en) * | 2001-11-23 | 2003-10-31 | Glaxo Group Ltd | Pharmaceutical composition |
| AU2003276525A1 (en) * | 2002-11-15 | 2004-06-15 | Orchid Chemicals And Pharmaceuticals Ltd | Novel amorphous hydrate of a cephalosporin antibiotic |
| CN100448879C (en) * | 2004-07-22 | 2009-01-07 | 北京化工大学 | Method for preparing unformed cefuroxime axetil |
| EP3169669A1 (en) * | 2014-07-15 | 2017-05-24 | OLON S.p.A. | Amorphous form and new crystalline forms of macitentan |
| CN116284050B (en) * | 2022-12-19 | 2024-04-12 | 华北制药河北华民药业有限责任公司 | Method for converting high-efficiency crystalline cefuroxime axetil into amorphous powder and product |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1571683A (en) * | 1976-02-16 | 1980-07-16 | Glaxo Operations Ltd | Ester derivatives of cefuroxime |
| YU44680B (en) * | 1982-07-30 | 1990-12-31 | Glaxo Lab Ltd | Process for obtaining very pure amorphous form of cephuroxim axetile |
| IT1277426B1 (en) * | 1995-08-03 | 1997-11-10 | Acs Dobfar Spa | BIOAVAILABLE CRYSTALLINE FORM OF CEFUROXIMA AXETIL |
-
1996
- 1996-07-26 NZ NZ299077A patent/NZ299077A/en unknown
-
1997
- 1997-07-25 CA CA002211499A patent/CA2211499A1/en not_active Abandoned
- 1997-07-25 US US08/900,669 patent/US5847118A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NZ299077A (en) | 1998-06-26 |
| US5847118A (en) | 1998-12-08 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |